Arylsulfonamide ccr3 antagonists

Abstract

Provided herein are arylsulfonamides that are useful for modulating CCR3 activity, and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a CCR3-mediated disorder, disease, or condition.

1 . A compound of Formula II: 
       
         
           
           
               
               
           
         
         or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; 
         wherein:
 R 1 , R 2 , R 3 , R 4 , R 5 , and R 6  are each independently (a) hydrogen, halo, cyano, nitro, or guanidine; (b) C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(═NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a —C(O)OR 1d , —NR 1a —C(O)NR 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; 
 R 7  is (a) hydrogen, halo, cyano, nitro, oxo, or guanidine; (b) C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(═NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a —C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; 
 X is O or S; 
 Z is —C(O)R 1a , —C(S)R 1a , —C(O)NR 1b R 1c , —C(S)NR 1b R 1c , —S(O)R 1a  or —S(O) 2 R 1a ; 
 R 9  is hydrogen, C 1-6  alkyl or C 3-7  cycloalkyl; 
 m is an integer from 0 to 3; 
 n is an integer from 1 to 3; 
 p is an integer from 1 to 4; and 
 each R 1a , R 1b , R 1c , R 1d  and R 1e  is independently hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, heteroaryl, or heterocyclyl; or each pair of R 1b  and R 1c  together with the N atom to which they are attached independently form heteroaryl or heterocyclyl, with the proviso that R 1c  is not t-butyl or benzyl; 
 wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, and heteroaryl is optionally substituted with one or more groups, each independently selected from (a) cyano, halo, and nitro; (b) C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more, substituents Q; and (c) —C(O)R a , —C(O)OR a , —C(O)NR b R c , —C(NR a )NR b R c , —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR b R c , —OC(═NR a )NR b R c , —OS(O)R a , —OS(O) 2 R a , —OS(O)NR b R c , —OS(O) 2 NR b R c , —NR b R c , —NR a C(O)R d , —NR a —C(O)OR d , —NR a —C(O)NR b R c , —NR a C(═NR d )NR b R c , —NR a S(O)R d , —NR a S(O) 2 R d , —NR a S(O)NR b R c , —NR a S(O) 2 NR b R c , —SR a , —S(O)R a , —S(O) 2 R a , —S(O)NR b R c , and —S(O) 2 NR b R c , wherein each R a , R b , R c , and R d  is independently (i) hydrogen; (ii) C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) R b  and R c  together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q; 
 wherein each Q is independently selected from the group consisting of (a) deuterium; (b) cyano, halo, and nitro; (c) C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, and heterocyclyl; and (d) —C(O)R e , —C(O)OR e , —C(O)NR f R g , —C(NR e )NR f R g , —OR e , —OC(O)R e , —OC(O)OR e , —OC(O)NR f R g , —OC(═NR e )NR f R g , —OS(O)R e , —OS(O) 2 R e , —OS(O)NR f R g , —OS(O) 2 NR f R g , —NR f R g , —NR e C(O)R h , —NR e —C(O)OR h , —NR e —C(O)NR f R g , —NR e C(═NR h )NR f R g , —NR e S(O)R h , —NR e S(O) 2 R h , —NR e S(O)NR f R g , —NR e S(O) 2 NR f R g , —SR e , —S(O)R e , —S(O) 2 R e , —S(O)NR f R g , and —S(O) 2 NR f R g ; 
 wherein each R e , R f , R g , and R h  is independently (i) hydrogen; (ii) C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, or heterocyclyl; or (iii) R f  and R g  together with the N atom to which they are attached form heterocyclyl. 
 
       
     
     
         2 . The compound of  claim 1 , wherein
 R 1 , R 2 , R 3 , R 4 , and R 5  are each independently hydrogen, halo, or C 1-6  alkyl;   R 6  is cyano or nitro;   R 7  is hydrogen or C 1-6  alkyl;   X is O or S;   m is 0, 1, or 2;   n is 1 or 2;   p is 1, 2, 3, or 4; and   R 1a , R 1c , and R 1e  are each independently (a) C 1-6  alkyl, optionally substituted with one or more halo, C 1-6  alkoxy, C 1-6  alkylthio, heterocyclyl or heteroaryl; (b) C 2-6  alkenyl, optionally substituted with one or more halo; (c) C 3-7  cycloalkyl, optionally substituted with one or more halo, or one or two C 1-6  alkyl; (d) C 6-14  aryl, optionally substituted with one or more halo, C 1-6  alkyl, where the alkyl is further optionally substituted with one, two, or three halo or C 1-6  alkoxy, where the alkoxy is further optionally substituted with one, two, or three halo; (e) heteroaryl, optionally substituted with one or two C 1-6  alkyl; or (f) C 7-15  aralkyl optionally substituted with one or more halo, C 1-6  alkyl, where the alkyl is further optionally substituted with one, two, or three halo, or C 1-6  alkoxy, where the alkoxy is further optionally substituted with one, two, or three halo; and   R 1b  is hydrogen or methyl; or   R 1b  and R 1c  together with the N atom to which they are attached form heterocyclyl;   with the proviso that R 1e  is not t-butyl or benzyl.   
     
     
         3 . The compound of  claim 1 , wherein
 R 7  is hydrogen;   m is 1;   n is 1; and   p is 1, 2, 3, or 4.   
     
     
         4 - 9 . (canceled) 
     
     
         10 . The compound of  claim 1 , wherein
 R 1 , R 2 , R 3 , R 4 , and R 5  are each independently hydrogen, halo, or C 1-6  alkyl;   R 6  is cyano or nitro;   R 7  is hydrogen or C 1-6  alkyl;   R 9  is hydrogen or C 1-6  alkyl;   X is O or S;   m is 0, 1, or 2;   n is 1 or 2;   p is 1, 2, 3, or 4; and   Z is —C(O)R 1a , —C(S)R 1a , —C(O)NR 1b R 1c , —C(S)NR 1b R 1c , —C(O)OR 1e , —S(O)R 1a  or —S(O) 2 R 1a ; wherein   R 1a , R 1c  and R 1e  are each independently (a) C 1-6  alkyl, optionally substituted with one or more halo, C 1-6  alkoxy, C 1-6  alkylthio, heterocyclyl or heteroaryl; (b) C 2-6  alkenyl, optionally substituted with one or more halo; (c) C 3-7  cycloalkyl, optionally substituted with one or more halo, or one or two C 1-6  alkyl; (d) C 6-14  aryl, optionally substituted with one or more halo, C 1-6  alkyl, where the alkyl is further optionally substituted with one, two, or three halo or C 1-6  alkoxy, where the alkoxy is further optionally substituted with one, two, or three halo; (e) heteroaryl, optionally substituted with one or two C 1-6  alkyl; or (f) C 7-15  aralkyl optionally substituted with one or more halo, C 1-6  alkyl, where the alkyl is further optionally substituted with one, two, or three halo, or C 1-6  alkoxy, where the alkoxy is further optionally substituted with one, two, or three halo; and   R 1b  is hydrogen or methyl; or   R 1b  and R 1c  together with the N atom to which they are attached form heterocyclyl;   with the proviso that R 1e  is not t-butyl or benzyl.   
     
     
         11 . The compound of  claim 1 , wherein
 R 7  is hydrogen;   R 9  is hydrogen or methyl;   m is 1;   n is 1; and   Z is —C(O)R 1a  or —C(S)R 1a ; wherein   R 1a  is (a) C 1-6  alkyl, optionally substituted with one or more halo; (b) C 2-6  alkenyl;   (c) C 3-7  cycloalkyl; or (d) C 6-14  aryl, optionally substituted with one or more halo, C 1-6  alkyl or C 1-6  alkoxy.   
     
     
         12 . The compound of  claim 1 , wherein
 R 7  is hydrogen;   R 9  is hydrogen or methyl;   m is 1;   n is 1;   Z is —C(O)NR 1b R 1c  or —C(S)NR 1b R 1c ; wherein   R 1b  is hydrogen; and   R 1c  is (a) C 1-6  alkyl, optionally substituted with one or more halo or C 1-6  alkoxy, C 1-6  alkylthio, heterocyclyl or heteroaryl; (b) C 2-6  alkenyl; (c) C 3-7  cycloalkyl; or (d) C 6-14  aryl, optionally substituted with one or more halo, C 1-6  alkyl or C 1-6  alkoxy; and   R 1b  is hydrogen or methyl; or   R 1b  and R 1c  together with the N atom to which they are attached form heterocyclyl.   
     
     
         13 . The compound of  claim 1 , wherein
 R 7  is hydrogen;   R 9  is hydrogen or methyl;   m is 1;   n is 1; and   Z is —S(O) 2 R 1a ; wherein   R 1a  is (a) C 1-6  alkyl; (b) C 6-14  aryl, optionally substituted with one or more halo, C 1-6  alkyl or C 1-6  alkoxy; or (c) heteroaryl, optionally substituted with one or two C 1-6  alkyl.   
     
     
         14 . The compound of  claim 1 , wherein
 R 1  is hydrogen;   R 2  is chloro or methyl;   R 3  is hydrogen;   R 4  is chloro or methyl;   R 5  is hydrogen;   R 6  is cyano;   R 7  is hydrogen;   X is O or S;   m is 1; and   n is 1.   
     
     
         15 . The compound of  claim 1 , wherein two of R 1 , R 2 , R 3 , R 4 , and R 5  are halo or C 1-6  alkyl, and the remaining three are hydrogen. 
     
     
         16 . The compound of  claim 1 , wherein two of R 1 , R 2 , R 3 , R 4 , and R 5  are chloro or methyl, and the remaining three are hydrogen. 
     
     
         17 . The compound of  claim 1 , wherein X is O. 
     
     
         18 . The compound of  claim 1 , wherein X is S. 
     
     
         19 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers, and mixtures of two or more tautomers thereof; and pharmaceutically acceptable salts, solvates hydrates, and prodrugs thereof. 
       
     
     
         20 . A compound of Formula IIa: 
       
         
           
           
               
               
           
         
         or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. 
         wherein:
 R 1 , R 2 , R 3 , R 4 , R 5 , and R 6  are each independently (a) hydrogen, deuterium, halo, cyano, nitro, or guanidine; (b) C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(═NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a —C(O)OR 1d , —NR 1a —C(O)NR 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; 
 R 7  is (a) hydrogen, halo, cyano, nitro, oxo, or guanidine; (b) C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(═NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a —C(O)OR 1d , —NR 1a —C(O)NR 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; 
 X is O or S; 
 Z is —C(O)R 1a , —C(S)R 1a , —C(O)NR 1b R 1c , —C(S)NR 1b R 1c , —S(O)R 1a  or —S(O) 2 R 1a ; 
 R 9  is hydrogen, C 1-6  alkyl or C 3-7  cycloalkyl; 
 R d  is deuterium; 
 m is an integer from 0 to 3; 
 n is an integer from 1 to 3; 
 p is an integer from 1 to 4; and 
 q is an integer from 0 to 3. 
 each R 1a , R 1b , R 1c , R 1d  and R 1c  is independently hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, heteroaryl, or heterocyclyl; or each pair of R 1b  and R 1c  together with the N atom to which they are attached independently form heteroaryl or heterocyclyl, with the proviso that R 1e  is not t-butyl or benzyl; 
 wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, and heteroaryl is optionally substituted with one or more groups, each independently selected from (a) cyano, halo, and nitro; (b) C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more, substituents Q; and (c) —C(O)R a , —C(O)OR a , —C(O)NR b R c , —C(NR a )NR b R c , —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR b R c , —OC(═NR a )NR b R c , —OS(O)R a , —OS(O) 2 R a , —OS(O)NR b R c , —OS(O) 2 NR b R c , —NR b R c , —NR a C(O)R d , —NR a —C(O)OR d , —NR a —C(O)NR b R c , —NR a C(═NR d )NR b R c , —NR a S(O)R d , —NR a S(O) 2 R d , —NR a S(O)NR b R c , —NR a S(O) 2 NR b R c , —SR a , —S(O)R a , —S(O) 2 R a , —S(O)NR b R c , and —S(O) 2 NR b R c , wherein each R a , R b , R c , and R d  is independently (i) hydrogen; (ii) C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) R b  and R c  together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q; 
 wherein each Q is independently selected from the group consisting of (a) deuterium; (b) cyano, halo, and nitro; (c) C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, and heterocyclyl; and (d) —C(O)R e , —C(O)OR e , —C(O)NR f R g , —C(NR e )NR f R g , —OR e , —OC(O)R e , —OC(O)OR e , —OC(O)NR f R g , —OC(═NR e )NR f R g , —OS(O)R e , —OS(O) 2 R e , —OS(O)NR f R g , —OS(O) 2 NR f R g , —NR f R g , —NR e C(O)R h , —NR e —C(O)OR h , —NR e —C(O)NR f R g , —NR e C(═NR h )NR f R g , —NR e S(O)R h , —NR e S(O) 2 R h , —NR e S(O)NR f R g , —NR e S(O) 2 NR f R g , —SR e , —S(O)R e , —S(O) 2 R e , —S(O)NR f R g , and —S(O) 2 NR f R g ; 
 wherein each R e , R f , R g , and R h  is independently (i) hydrogen; (ii) C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, or heterocyclyl; or (iii) R f  and R g  together with the N atom to which they are attached form heterocyclyl. 
 
       
     
     
         21 - 23 . (canceled) 
     
     
         24 . The compound of  claim 20 , wherein the compound is of formula IIa and wherein:
 R 1 , R 2 , R 3 , R 4 , and R 5  are each independently hydrogen, deuterium, halo, or C 1-6  alkyl;   R 6  is cyano or nitro;   R 7  is hydrogen or C 1-6  alkyl;   R 9  is hydrogen or C 1-6  alkyl;   R d  is deuterium;   X is O or S;   m is 0, 1, or 2;   n is 1 or 2;   p is 1, 2, 3, or 4; and   q is 3; and   Z is —C(O)R 1a , —C(S)R 1a , —C(O)NR 1b R 1c , —C(S)NR 1b R 1c , —C(O)OR 1e , —S(O)R 1a  or —S(O) 2 R 1a ; wherein   R 1a , R 1c  and R 1e  are each independently (a) C 1-6  alkyl, optionally substituted with one or more halo, C 1-6  alkoxy, C 1-6  alkylthio, heterocyclyl or heteroaryl; (b) C 2-6  alkenyl, optionally substituted with one or more halo; (c) C 3-7  cycloalkyl, optionally substituted with one or more halo, or one or two C 1-6  alkyl; (d) C 6-14  aryl, optionally substituted with one or more halo, C 1-6  alkyl, where the alkyl is further optionally substituted with one, two, or three halo or C 1-6  alkoxy, where the alkoxy is further optionally substituted with one, two, or three halo; (e) heteroaryl, optionally substituted with one or two C 1-6  alkyl; or (f) C 7-15  aralkyl optionally substituted with one or more halo, C 1-6  alkyl, where the alkyl is further optionally substituted with one, two, or three halo, or C 1-6  alkoxy, where the alkoxy is further optionally substituted with one, two, or three halo; and   R 1b  is hydrogen or methyl; or   R 1b  and R 1c  together with the N atom to which they are attached form heterocyclyl.   
     
     
         25 . The compound of  claim 1 , wherein the compound is a hydrochloride salt. 
     
     
         26 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt, hydrate, stereoisomer, or tautomer thereof; and one or more pharmaceutically acceptable carriers or excipients. 
     
     
         27 . The pharmaceutical composition of  claim 26 , further comprising a therapeutic agent. 
     
     
         28 . The pharmaceutical composition of  claim 26 , wherein the composition is formulated for single dose administration. 
     
     
         29 . The pharmaceutical composition of  claim 28 , wherein the composition is formulated as oral, parenteral, or intravenous dosage form. 
     
     
         30 . The pharmaceutical composition of  claim 29 , wherein the oral dosage form is a tablet or capsule. 
     
     
         31 . A method for the treatment, prevention, or amelioration of one or more symptoms of a CCR3-mediated disorder, disease, or condition in a subject, which comprises administering to the subject a therapeutically effective amount of the compound of  claim 1 . 
     
     
         32 . A method for the treatment, prevention, or amelioration of one or more symptoms of an eosinophil-related disorder, disease, or condition in a subject, which comprises administering to the subject a therapeutically effective amount of the compound of  claim 1 . 
     
     
         33 . A method for the treatment, prevention, or amelioration of one or more symptoms of a basophil-related disorder, disease, or condition in a subject, which comprises administering to the subject a therapeutically effective amount of the compound of  claim 1 . 
     
     
         34 . A method for the treatment, prevention, or amelioration of one or more symptoms of a mast cell-related disorder, disease, or condition in a subject, which comprises administering to the subject a therapeutically effective amount of the compound of  claim 1 . 
     
     
         35 . A method for the treatment, prevention, or amelioration of one or more symptoms of an inflammatory disease in a subject, which comprises administering to the subject a therapeutically effective amount of the compound of  claim 1 . 
     
     
         36 . The method of  claim 31 , wherein the disorder, disease, or condition is selected from the group consisting of asthma, allergic asthma, exercise induced asthma, allergic rhinitis, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity, contact dermatitis, conjunctivitis, allergic conjunctivitis, eosinophilic bronchitis, food allergies, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, mastocytosis, hyper IgE syndrome, systemic lupus erythematous, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury, Churg-Strauss syndrome, sinusitis, basophilic leukemia, chronic urticaria, basophilic leukocytosis, eczema, COPD (chronic obstructive pulmonary disorder), arthritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, and cardiovascular disorders. 
     
     
         37 . The method of  claim 36 , wherein the disorder, disease, or condition is asthma, exercise induced asthma, allergic rhinitis, atopic dermatitis, chronic obstructive pulmonary disease, or allergic conjunctivitis. 
     
     
         38 . The method of  claim 31 , wherein the compound is administered orally, parenterally, or topically. 
     
     
         39 . The method of  claim 31 , wherein the compound is administered in combination with a second therapeutic agent. 
     
     
         40 . A method for modulating CCR3 activity, comprising contacting a CCR3 receptor with the compound of  claim 1 .